The gamma-herpesviruses, including EBV and KSHV, are persistent, oncogenic human pathogens that are widely disseminated in the population and are associated with human disease ranging from infectious mononucleosis to several malignancies. An important goal is the development of preventative vaccines. We have taken advantage of an experimental model, murine gamma-herpesvirus-68 (MHV-68), to dissect early events in the viral infection, to characterize the cellular and humoral immune response, and to test vaccination strategies. Our earlier vaccination studies have shown that vaccination can reduce the lytic load, but have so far failed to prevent the establishment of latency. However, new preliminary data show that latent infection is established in the lung as early as three days after infection, suggesting that efficient vaccines must quickly target infectious virus and lytically- and latently-infected cells in the lung. Based on these observations and recent advances in the field of T cell memory, we hypothesize that vaccination strategies emphasizing pulmonary immunity to both lytic and latent antigens will generate strong protective immunity. In addition, preliminary data showing that the presence of neutralizing antibody at the time of infection greatly reduced the peak lytic load suggests that neutralizing antibody may augment protective cellular immunity by controlling viral titers during the protective recall T cell response. The goal of the current studies is to characterize epitope expression (Aim 1) and virus-specific T cells (Aim 2) during acute and latent MHV-68 infection. In Aim 3, we will build on this information and use this well-characterized viral model as a "proof of principal" test for epitope-based vaccination strategies for the gamma-herpesviruses. [unreadable] [unreadable] [unreadable]